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PNAS:用于增强顺铂化疗功效的纳米粒

来源:生物谷 2014-07-10 09:01

2014年7月10日讯 /生物谷BIOON/--近日,佐治亚大学研究人员对传统化疗药物顺铂进行修改,开发出一种前体药物,能显著加强顺铂瞄准并摧毁癌细胞的能力。

顺铂可用于治疗多种癌症,它是膀胱癌,卵巢癌,宫颈癌,睾丸癌和肺癌最常用的化疗药物。虽然它是一种有效的药物,但许多癌细胞对此产生耐药性。

最新科学家成功制造出顺铂的修改版本,称为铂-M(Platin-M),铂-M目的是通过攻击癌细胞线粒体来克服这种耐药性。相关研究发表在PNAS杂志上。

癌细胞的生长和增殖需要线粒体提供能量,新创造的前体药物能直接递送顺铂到癌细胞线粒体中。如果没有这些线粒体,癌细胞就无法生存。

将铂-M包埋在一个专门设计的纳米颗粒中,此纳米颗粒比人的头发细1000倍,纳米颗粒到达线粒体、释放出药物(顺铂)。一旦进入线粒体,铂-M干扰线粒体的DNA,引发癌细胞死亡。

研究小组测试了铂-M在神经母细胞瘤中的功效。在使用顺铂耐药细胞实验中,铂-M纳米颗粒比单独使用顺铂的活性高出17倍。

这种新技术可能成为许多癌症的新治疗药物,但实验结果是初步的,在铂-M进入任何临床试验前还需进一步研究。(生物谷Bioon.com)

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Shanta Dhar et al.

Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strain-promoted alkyne–azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ~17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy.

 

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